A hypothalamic dopamine locus for psychostimulant-induced hyperlocomotion in mice.

The lateral septum (LS) has been implicated in the regulation of locomotion. Nevertheless, the neurons synchronizing LS activity with the brain's clock in the suprachiasmatic nucleus (SCN) remain unknown. By interrogating the molecular, anatomical and physiological heterogeneity of dopamine neurons of the periventricular nucleus (PeVN; A14 catecholaminergic group), we find that Th+/Dat1+ cells from its anterior subdivision innervate the LS in mice. These dopamine neurons receive dense neuropeptidergic innervation from the SCN. Reciprocal viral tracing in combination with optogenetic stimulation ex vivo identified somatostatin-containing neurons in the LS as preferred synaptic targets of extrahypothalamic A14 efferents. In vivo chemogenetic manipulation of anterior A14 neurons impacted locomotion. Moreover, chemogenetic inhibition of dopamine output from the anterior PeVN normalized amphetamine-induced hyperlocomotion, particularly during sedentary periods. Cumulatively, our findings identify a hypothalamic locus for the diurnal control of locomotion and pinpoint a midbrain-independent cellular target of psychostimulants.

Unconventional superconductivity and interaction induced Fermi surface reconstruction in the two-dimensional Edwards model.

We study the competition between unconventional superconducting pairing and charge density wave (CDW) formation for the two-dimensional Edwards Hamiltonian at half filling, a very general two-dimensional transport model in which fermionic charge carriers couple to a correlated background medium. Using the projective renormalization method we find that a strong renormalization of the original fermionic band causes a new hole-like Fermi surface to emerge near the center of the Brillouin zone, before it eventually gives rise to the formation of a charge density wave. On the new, disconnected parts of the Fermi surface superconductivity is induced with a sign-changing order parameter. We discuss these findings in the light of recent experiments on iron-based oxypnictide superconductors.

Occular and dermal toxicity of Jatropha curcas phorbol esters.

Jatropha curcas seeds are a promising feedstock for biodiesel production. However, Jatropha seed oil and other plant parts are toxic due to the presence of phorbol esters (PEs). The ever-increasing cultivation of toxic genotype of J. curcas runs the risk of increased human exposure to Jatropha products. In the present study, effects of J. curcas oil (from both toxic and nontoxic genotypes), purified PEs-rich extract and purified PEs (factors C1, C2, C(3mixture), (C4+C5)) on reconstituted human epithelium (RHE) and human corneal epithelium (HCE) were evaluated in vitro. The PEs were purified from toxic Jatropha oil. In both RHE and HCE, the topical application of PEs containing samples produced severe cellular alterations such as marked oedema, presence of less viable cell layers, necrosis and/or partial tissue disintegration in epithelium and increased inflammatory response (interleukin-1α and prostaglandin E2). When compared to toxic oil, histological alterations and inflammatory response were less evident (P<0.05) in nontoxic oil indicating the severity of toxicity was due to PEs. Conclusively, topical applications of Jatropha PEs are toxic towards RHE and HCE models, which represents dermal and occular toxicity respectively. Data obtained from this study would aid in the development of safety procedures for Jatropha biodiesel industries. It is advised to use protective gloves and glasses when handling PEs containing Jatropha products.

Pharmaceutical potential of phorbol esters from Jatropha curcas oil.

Phorbol esters (PEs) are diterpenes present in Jatropha curcas L. seeds and have a myriad of biological activities. Since PEs are toxic, they are considered to be futile in Jatropha-based biodiesel production chain. In the present study, the extracted PEs from Jatropha oil were used as a starting material to synthesise pharmacologically important compound, prostratin. The prostratin synthesised from Jatropha showed identical mass with that of the reference standard prostratin, as determined by Nano-LC-ESI-MS/MS. Considering the rapid growth in Jatropha biodiesel industry, potential exists to harness large amount of PEs which can be further utilised to synthesise prostratin as a value added product.

Chemical characterisation of kernels, kernel meals and oils from Jatropha cordata and Jatropha cardiophylla seeds.

BACKGROUND: Jatropha cordata and Jatropha cardiophylla are native to northwestern Mexico and are adapted to arid and semi-arid conditions (<500 mm of precipitation and temperatures from 8 to 45 °C). The aim of this study was to evaluate the chemical composition of J. cordata and J. cardiophylla kernels and oils as well as antinutrients in the defatted kernel meals of these species. RESULTS: Kernels of J. cordata and J. cardiophylla seeds analysed in this study were rich in crude protein (283 and 289 g kg(-1) respectively) and lipid (517 and 537 g kg(-1) respectively). The main fatty acids in J. cordata and J. cardiophylla oils were linoleic and oleic acids. High levels of trypsin inhibitor and phytates and low levels of saponins were present in the meals. The phorbol ester contents in J. cordata and J. cardiophylla kernel meals were 2.73 and 1.46 mg g(-1) respectively. CONCLUSION: For both J. cordata and J. cardiophylla it could be inferred that (a) the oil and kernel meal were toxic and the kernel meal could be used as livestock feed only after detoxification, (b) the oil could be used for non-alimentary purposes, i.e. biodiesel production, and (c) the seed or oil could be used for isolating various bioactive compounds for pharmaceutical and agricultural applications.

Isolation, stability and bioactivity of Jatropha curcas phorbol esters.

Jatropha curcas seed oil, which can be utilized for biodiesel production upon transesterification, is also rich in phorbol esters (PEs). In this study, PEs from J. curcas oil (Jatropha factors C1 and C2 (purified to homogeneity), Jatropha factors C3 and (C4+C5) (obtained as mixtures) and PE-rich extract (containing all the above stated Jatropha factors) were investigated. The concentrations of Jatropha PEs were expressed equivalent to Jatropha factor C1. In the snail (Physa fontinalis) bioassay, the order of potency (EC50, µg/L) was: PE-rich extract

Localisation of antinutrients and qualitative identification of toxic components in Jatropha curcas seed.

BACKGROUND: Jatropha curcas seed oil is a promising feedstock for biodiesel production. The seeds contain major toxic (phorbol esters, PEs) and antinutritional (phytate and trypsin inhibitor) factors. In the present study the localisation of antinutrients and a rapid qualitative method for detecting the presence of PEs were investigated. RESULTS: Kernels were separated into cotyledon, hypocotyl, kernel coat and endosperm. The majority of phytate (96.5%), trypsin inhibitor (95.3%) and PEs (85.7%) were localised in the endosperm. Based on PEs, a qualitative method was developed to differentiate between toxic and non-toxic Jatropha genotypes. In this method, PEs were easily detected by passing methanol extracts of kernels (Jatropha toxic and non-toxic genotypes) through a solid phase extraction (SPE) column and measuring the absorption of the resulting eluates at 280 nm. For raw kernels, SPE eluates with absorbance ≥ 0.056 were considered as toxic and those with absorbance ≤0.032 as non-toxic. For defatted kernel meals, SPE eluates with absorbance ≥ 0.059 were considered as toxic and those with absorbance ≤0.043 as non-toxic. CONCLUSION: The majority of antinutrients/toxic compounds are localised in the endosperm of the kernel. The qualitative method developed for rapid identification of toxic PEs could be useful in screening the toxicity of Jatropha-based products in the biodiesel industry. Further confirmation of PEs should be established by high-performance liquid chromatography.

Isolation of phytate from Jatropha curcas kernel meal and effects of isolated phytate on growth, digestive physiology and metabolic changes in Nile tilapia (Oreochromis niloticus L.).

Jatropha curcas seeds are rich in oil and protein. The oil is used for biodiesel production. The defatted Jatropha kernel meal obtained after oil extraction is rich in protein (58-66%) and phytate (9-11%). The phytate rich fraction was isolated from defatted kernel meal using organic solvents (acetone and carbon tetracholride). It had 66% phytate and 22% crude protein. The fingerlings (n=50, 16.2 ± 0.64 g) were randomly distributed into five groups containing 10 replicates and fed iso-nitrogenous diets (crude protein 36%): control diet containing casein and gelatin as proteins; control diet containing 1.5% and 3% Jatropha phytate (PWP(1.5) and PWP(3), respectively); and control diet containing 1.5% and 3% Jatropha phytate supplemented with phytase (1500 FTU/kg) (PWP(1.5+Phytase) and PWP(3+Phytase), respectively). Significantly lower (P<0.05) growth and feed utilization in PWP(1.5) and PWP(3) groups than for control and both phytase containing groups were observed; whereas feed gain ratio exhibited opposite trend. Protein and lipid digestibilities of the diets, amylase and protease enzyme activities in the intestine were significantly higher (P<0.05) in PWP(1.5+Phytase) and PWP(3+Phytase) groups than for PWP(1.5) and PWP(3) groups. Lowest red blood cell counts, and hemoglobin and hematocrit concentrations were observed in PWP(3) group which were not statistically different to those for PWP(1.5) group, but were significantly (P<0.05) lower than those for all other groups. Highest albumin, globulin and total protein concentrations were observed in PP(3+Phytase) group and lowest in PWP(1.5) group; and values for the latter were statistically similar to those for control group. Calcium, phosphorus and glucose concentrations in blood and cholesterol concentration in plasma were significantly lower (P<0.05) in the phytate enriched groups compared with control and phytase treated groups (PP(1.5+Phytase) and PP(3+Phytase)). Higher (P<0.05) alkaline phosphatase activity was observed in phytase supplemented groups compared with that in non-supplemented groups which (PP(1.5+Phytase)) was statistically similar to that in control group, whereas alanine transaminase activity in blood exhibited opposite trend. In conclusion, Jatropha phytate present in DJKM is an antinutrient and addition of phytase in the diet containing DJKM is recommended.

Jatropha toxicity--a review.

Jatropha is a nonedible oil seed plant belonging to Euphorbiaceae family. Global awareness of sustainable and alternative energy resources has propelled research on Jatropha oil as a feedstock for biodiesel production. During the past two decades, several cultivation projects were undertaken to produce Jatropha oil. In future, the increased cultivation of toxic Jatropha plants and utilization of its agro-industrial by-products may raise the frequency of contact with humans, animals, and other organisms. An attempt was thus made to present known information on toxicity of Jatropha plants. The toxicity of Jatropha plant extracts from fruit, seed, oil, roots, latex, bark, and leaf to a number of species, from microorganisms to higher animals, is well established. Broadly, these extracts possess moluscicidal, piscicidal, insecticidal, rodenticidal, antimicrobial, and cytotoxic properties, and exert adverse effects on animals including rats, poultry, and ruminants. The toxicity attributed to these seeds due to their accidental consumption by children is also well documented. An attempt was also made to identify areas that need further study. The information provided in this review may aid in enhancing awareness in agroindustries involved in the cultivation, harvesting, and utilization of Jatropha plants and its products with respect to the potential toxicity of Jatropha, and consequently in application and enforcement of occupational safety measures. Data on the wide range of bioactivities of Jatropha and its products were collated and it is hoped will create new avenues for exploiting these chemicals by the phamaceutical industry to develop chemotherapeutic agents.

Nutritional, biochemical, and pharmaceutical potential of proteins and peptides from jatropha: review.

Increased bioenergy consciousness and high demand for animal products have propelled the search for alternative resources that could meet the dual demands. Jatropha seeds have potential to fit these roles in view of their multipurpose uses, broad climatic adaptability features, and high oil and protein contents. During the past five years many large-scale cultivation projects have been undertaken to produce jatropha seed oil as a feedstock for the biodiesel industry. The present review aims at providing biological significance of jatropha proteins and peptides along with their nutritional and therapeutic applications. The nutritional qualities of the kernel meal and protein concentrates or isolates prepared from seed cake are presented, enabling their efficient use in animal nutrition. In addition, (a) biologically active proteins involved in plant protection, for example, aquaporin and betaine aldehyde dehydrogenase, which have roles in drought resistance, and beta-glucanase, which has antifungal activity, as well as those having pharmaceutical properties, and (b) cyclic peptides with various biological activities such as antiproliferative, immunomodulatory, antifungal, and antimalarial activity are discussed. It is expected that the information collated will open avenues for new applications of proteins present in jatropha plant, thereby contributing to enhance the financial viability and sustainability of a jatropha-based biodiesel industry.

Phase I/II dose-escalation study of pemetrexed plus irinotecan in patients with advanced colorectal cancer.

BACKGROUND: Pemetrexed and irinotecan have demonstrated antitumor activity as single agents in lung, pancreatic, breast, and colorectal cancer (CRC). The distinct mechanisms of action and patterns of resistance displayed by pemetrexed and irinotecan make them attractive agents for combination therapy. PATIENTS AND METHODS: This phase I/II, nonrandomized, open-labeled, single-arm study was composed of 3 segments. The initial phase II portion of the study enrolled 23 patients with advanced CRC who had received 1 previous dose of 5-fluorouracil (5-FU)-based chemotherapy for advanced disease. Because of poorer than anticipated efficacy, a phase I dose-escalation study using vitamin supplementation (n = 12) was added to the original protocol. The phase II dose-escalation portion of the study enrolled 36 patients (64% with previous oxaliplatin-based therapy) who received pemetrexed 500 mg/m2 followed by irinotecan 300 mg/m2 on day 1, every 21 days. RESULTS: For the 35 evaluable patients in the phase II dose-escalation study, the objective response rate was 11.4% (95% confidence interval, 3.2%-26.7%); there was 1 patient with a complete response, 3 with partial responses, and 17 with stable disease. Three of four responders had received previous oxaliplatin-based combination therapy. Grade 3/4 hematologic toxicities included leukopenia (5.6%), anemia (2.8%), and thrombocytopenia (2.8%). Grade 3/4 nonhematologic toxicities included diarrhea (11.1%), increased aminotransferase levels (8.3%), nausea (8.3%), febrile neutropenia (5.6%), vomiting (5.6%), and reduced creatinine clearance (2.8%). CONCLUSION: Pemetrexed plus irinotecan appears to be at least as active as FOLFIRI (leucovorin/5-FU/irinotecan) for second-line therapy of CRC following 5-FU-based combination chemotherapy. Further studies are warranted.

Exposure of tilapia pituitary cells to saponins: insight into their mechanism of action.

Cell permeation and durable effects of triterpenoidal saponin preparations from soybean (SbS), Quillaja saponaria Molina (QsS) and Gypsophila paniculata (GypS), were studied. A concentration-dependent change in hemolysis rates was observed when cells were incubated with QsS or GypS, but not with SbS. Dose dependence was also observed for the leakage of lactate dehydrogenase (LDH; MW 142,000) and of Luteinizing Hormone (LH; MW 35,000) from tilapia pituitary dispersed cells. Exposure of pituitary fragments to a combination of GnRH and GypS or QsS, resulted in a significantly high release of LH. GypS were shown to be more potent in inducing hemolysis of human RBC's and LH release from tilapia pituitary fragments. Interestingly, tilapia pituitary fragments treated with QsS were able to secrete LH in a characteristic manner, in response to a second Gonadotropin Releasing Hormone (GnRH) pulse, while fragments exposed to GypS did not respond to the second hormone pulse. The rapid recovery of pituitary fragments after the removal of QsS, may suggest a rearrangement of membranes rather than pore formation as the mechanism of action of QsS. Understanding the structural features underlying the reversible rearrangement of membranes and the lack of hemolysing activity by specific saponins may lead to the development of novel bioactive drugs.

Antioxidant properties of various solvent extracts of total phenolic constituents from three different agroclimatic origins of drumstick tree (Moringa oleifera Lam.) leaves.

Water, aqueous methanol, and aqueous ethanol extracts of freeze-dried leaves of Moringa oleifera Lam. from different agroclimatic regions were examined for radical scavenging capacities and antioxidant activities. All leaf extracts were capable of scavenging peroxyl and superoxyl radicals. Similar scavenging activities for different solvent extracts of each collection were found for the stable 1,1-diphenyl 2-picrylhydrazyl (DPPH(*)) radical. Among the three different moringa samples, both methanol and ethanol extracts of Indian origins showed the highest antioxidant activities, 65.1 and 66.8%, respectively, in the beta-carotene-linoleic acid system. Nonetheless, increasing concentration of all the extracts had significantly (P < 0.05) increased reducing power, which may in part be responsible for their antioxidant activity. The major bioactive compounds of phenolics were found to be flavonoid groups such as quercetin and kaempferol. On the basis of the results obtained, moringa leaves are found to be a potential source of natural antioxidants due to their marked antioxidant activity. This is the first report on the antioxidant properties of the extracts from freeze-dried moringa leaves. Overall, both methanol (80%) and ethanol (70%) were found to be the best solvents for the extraction of antioxidant compounds from moringa leaves.

Effects of long term feeding of Quillaja saponins on sex ratio, muscle and serum cholesterol and LH levels in Nile tilapia (Oreochromis niloticus (L)).

Seventeen-day-old Nile tilapia fry were fed a standard diet (C) or diets containing 50-700 mg kg(-1) Quillaja saponin (QS) extract (groups S50, S150, S300, S500 and S700). After the first 8 weeks, 30 randomly selected tilapia from each of the treatments were placed in separate aquaria and fed the standard diet without saponins from then on (these were designated S50/C, S150/C, S300/C, S500/C and S700/C). The fish grew from an initial average weight of approximately 30 mg to a final average weight of 79 g during the 6-month feeding period. The difference between the average weight of C-fed tilapia and the treatment with the highest average weight after 6 months was 53.5%. The sex ratio of tilapia in the saponin-fed groups deviated from the normal 50:50 male:female ratio, with the S700 group showing a significantly higher number of males. Quillaja saponin stimulated LH release from dispersed tilapia pituitary cells in vitro. This effect was abolished in the presence of dilute calf serum. Serum LH values did not show any diet-dependent trend in either male or female tilapia in vivo. In both continuously saponin-fed and only-initially saponin-fed groups, the average serum (but not muscle) cholesterol levels in males showed an increasing trend (R(2) values of 0.62 and 0.69) with increasing dietary saponin level. It was concluded that dietary QS has the potential to change the sex-ratio in favour of males. More investigations are required to determine the mechanism of action and the optimum dietary level of QS for maximum effects.

Microcystins in natural blooms and laboratory cultured Microcystis aeruginosa from Laguna de Bay, Philippines.

Laguna de Bay, the largest freshwater lake in the Philippines, experiences periodic blooms of the cyanobacteria Microcystis aeruginosa. Blooms of these cyanobacteria in 1996, 1998 and 1999 were sampled. HPLC and MALDI-TOF mass spectrometry were used to analyze for microcystins. A total of 16 structural variants of the toxin were isolated from the samples with microcystin LR (MC-LR) as the most abundant variant in the samples from 1996 and 1999 making up 77 to 85% of the total, respectively. MC-RR was the dominant variant in the 1998 bloom making up 38%. The samples from 1996 had the highest total toxin concentration (4049 microg g(-1)) followed by those from 1998 (1577 microg g(-1)) and 1999 (649 microg g(-1)). A strain of M. aeruginosa previously isolated from the lake was also cultured in the laboratory under different nitrogen concentrations (1, 3 and 6 mg L(-1)) and elevated phosphorus concentration (0.5 mg L(-1)) to determine the influence of these factors on toxin production. A total of 9 different structural variants of microcystin were isolated from the laboratory cultures with MC-LR consisting more than 75% of the total in all treatments. No significant differences in the total toxin concentration as well as the % distribution of the different variants among treatments were observed. However, the strain of M. aeruginosa cultured in the laboratory had from 3 to 20 times higher total microcystin than those harvested from the lake.